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Background  Intrauterine exposure to maternal smoking is linked to impaired executive function and behavioral problems in the offspring. Maternal smoking is associated with reduced fetal brain growth and smaller volume of cortical gray matter in childhood, indicating that prenatal exposure to tobacco may impact cortical development and manifest as behavioral problems. Cellular development is mediated by changes in epigenetic modifications such as DNA methylation, which can be affected by exposure to tobacco.    Results  In this study, we sought to ascertain how maternal smoking during pregnancy affects global DNA methylation profiles of the developing dorsolateral prefrontal cortex (DLPFC) during the second trimester of gestation. When DLPFC methylation profiles (assayed via Illumina, HM450) of smoking-exposed and unexposed fetuses were compared, no differentially methylated regions (DMRs) passed the false discovery correction (FDR ≤ 0.05). However, the most significant DMRs were hypomethylated CpG Islands within the promoter regions of  GNA15  and  SDHAP3  of smoking-exposed fetuses. Interestingly, the developmental up-regulation of  SDHAP3  mRNA was delayed in smoking-exposed fetuses. Interaction analysis between gestational age and smoking exposure identified significant DMRs annotated to  SYCE3 ,  C21orf56 / LSS, SPAG1  and  RNU12 / POLDIP3  that passed FDR. Furthermore, utilizing established methods to estimate cell proportions by DNA methylation, we found that exposed DLPFC samples contained a lower proportion of neurons in samples from fetuses exposed to maternal smoking. We also show through in vitro experiments that nicotine impedes the differentiation of neurons independent of cell death.    Conclusions  We found evidence that intrauterine smoking exposure alters the developmental patterning of DNA methylation and gene expression and is associated with reduced mature neuronal content, effects that are likely driven by nicotine.    Electronic supplementary material  The online version of this article (doi:10.1186/s13072-017-0111-y) contains supplementary material, which is available to authorized users.

In utero exposure to maternal smoking is associated with DNA methylation alterations and reduced neuronal content in the developing fetal brain